Table 1.

Overview of molecular mechanisms in bone resorption in thalassemia

Factors	Target (pathway/gene)	Role
PTH	PKA activation and down regulation ofOPG/RANKL ratio	Osteoclast activation
17OH-estradiol	Down regulation of JNK pathway onRANKL downstream	Reduction of osteoclast differentiation
Estrogen andtestosterone	Influence on OPG and RANKL mRNA	Up regulation of OPG/RANKL ratio
Estrogen	RUNX2 activation	Osteoblastic differentiation
	Fasl activation	Osteoclast apoptosis
IL-1α, IL-6, TNF-α	Initiation of the NF-κB pathway	Increased osteoclast differentiationand activation
TGF-β	Activation of Smad pathway andinduced RUNX2 production	Osteoblast differentiation
		IGF-1	Increased OPG, collagen type I, RUNX2,ALP production in HMSC	Osteoblastic differentiation
GH	Increased OPG	Inhibition of osteoclasto-genesis
	Increased BMP2	Induction of osteoblastic differentiation
BMP2	Elevated β-catenin level thatresults in CBF-α transcription	Osteoblasticdifferentiation
RUNX2	Wnt canonical pathway	Osteoblastic differentiation
Wnt/βcateninsignaling pathway	β-catenin stabilization	Osteoblastic differentiation
	Up regulation of OPG/RANKL ratio	Reduction of osteoclastic differentiation
DKK-1	Antagonizes canonical Wnt signaling byinhibiting LRP5/6 interaction with Wnt	Inhibition of osteoblastic differentiation
SOST	Inhibition of Wnt signaling	Inhibition of osteoblastic differentiation

PTH; Parathyroid hormone, PKA; Protein kinase A, TGF-β; Transforming growth factor-beta, SOST; Sclerostin, DKK-1; Dickkopf, BMP2; Bone morphogenetic protein 2, GH; Growth hormone, IGF-1; Insulin-like growth factor 1, Wnt; Wingless related protein, LRP5; Low density lipoprotein (LDL)-related protein 5, OPG; Osteoprotegrin, RANX2; Runt-related transcription factor 2, JNK; Janus kinase, ALP; alkaline phosphatase, HMSC; Human mesenchymal stem cells, NF-κB; Nuclear factor kappa B, RANKL; Activator of NF-κB receptor ligand, TNF-α; Tumor necrotic factor-alpha, IL-6; Interlukin-6 and IL-1α; Interlukin-1 alpha.